Genetic Linkages in Calcium Oxalate Stone Disease

描述（由申请人提供）：肾结石疾病是一种严重的健康问题，与严重的疼痛，痛苦和经济成本相关。5%至15%的人口在70岁时会出现结石症状，其中至少50%的人会复发。迄今为止，导致高尿酸和草酸钙结石病的唯一明确的遗传异常已被描述为原发性和继发性高尿酸，并与特定的酶错误。然而，特发性草酸钙结石病的家族性倾向加上结石复发的共同趋势，导致推测许多特发性草酸钙结石形成者可能具有结石病的遗传易感性。我们建议探索特发性高血压尿和草酸钙结石病的遗传联系，利用和应用于结石病的方法和遗传观察，从现有的动物模型，目前正在使用，以探索高血压的遗传基础。基因组学方法在结石病中的应用是新的。拟议的研究将使我们能够确定介导特发性草酸钙结石病的关键机制事件的遗传联系，包括高尿酸血症、晶体形成和草酸钙晶体潴留的发生、进展和生理后果。 我们将利用现有的大鼠基因组资源来探索草酸钙结石病的遗传联系以及草酸钙结石病和高血压之间的遗传联系。将使用三个特定的主要育种菌落：1）证明盐敏感性高血压的Dahl SS大鼠，2）与Dahl SS大鼠约62%同源的Brown Norway大鼠群，和3）Dahl SS大鼠的同源品系，其每次具有一条染色体渗入来自Brown Norway大鼠的Dahl SS遗传背景中，产生与亲本Dahl大鼠约98%同源的大鼠。我们的工作假设是，特发性高血压尿症和草酸钙结石病与特定的遗传连锁有关，并且与高血压相关的结石病的病理生理学不同于无高血压的结石病。有三个具体目标。 具体目标一：确定高血压和高尿酸对尿化学的相关影响以及这些相关挑战如何影响草酸钙结石病的可能性。 具体目标二：明确与高血压和高尿酸挑战相关的特定组织损伤，并将这些发现与有效的草酸钙晶体附着和结石成熟相关。 具体目标三：使用染色体置换组的consomic Dahl SS大鼠，鉴定携带控制高尿酸、草酸钙结晶症和结石病的主要易感性和抗性基因的染色体。

DESCRIPTION (provided by applicant): Kidney stone disease is a substantial health problem associated with significant pain, suffering, and economic costs. 5% to 15% of the population will have a symptomatic episode of a stone by the age of 70 and at least 50% of these individuals will have recurrent disease. To date, the only well-defined genetic abnormalities leading to hyperoxaluria and calcium oxalate stone disease have been described for primary and secondary hyperoxaluria and associated with specific enzyme errors. However, the familial tendency of idiopathic calcium oxalate stone disease coupled with the common trend for stone recurrence have led to the speculation that many idiopathic calcium oxalate stone formers may have a genetic predisposition for their stone disease. We propose to explore the genetic linkages underlying idiopathic hyperoxaluria and calcium oxalate stone disease, utilizing and applying to stone disease the methods and genetic observations from existing animal models currently being used to explore the genetic basis of hypertension. The application of genomic methods to stone disease is new. The proposed studies will allow us to define the genetic linkages that mediate critical mechanistic events in idiopathic calcium oxalate stone disease including the initiation, progression, and physiologic consequences of hyperoxaluria, crystalluria, and calcium oxalate crystal retention. We will use available genomic rat resources to explore both the genetic linkages in calcium oxalate stone disease and the genetic linkages between calcium oxalate stone disease and hypertension. Three specific major breeding colonies will be used: 1) The Dahl SS rat that demonstrates salt sensitive hypertension, 2) A colony of Brown Norway rats that are about 62% consomic with the Dahl SS rat, and 3) Consomic strains of Dahl SS rats that have one chromosome at a time introgressed into the Dahl SS genetic background from the Brown Norway rat, creating a rat that is about 98% consomic with the parent Dahl rat. Our working hypothesis is that there are specific genetic linkages that are associated with idiopathic hyperoxaluria and calcium oxalate stone disease and that the pathophysiology of stone disease associated with hypertension is different from stone disease absent hypertension. There are three Specific Aims. Specific Aim I: To determine what the associative effect of hypertension and hyperoxaluria is on urine chemistry and how these associated challenges influence the potential for calcium oxalate stone disease. Specific Aim II: To define the specific tissue injury associated with hypertensive and with hyperoxaluric challenges and to correlate these findings with effective calcium oxalate crystal attachment and stone maturation. Specific Aim III: To identify the chromosomes that harbor genes that control major susceptibility and resistance to hyperoxaluria, calcium oxalate crystalluria, and stone disease using a chromosomal replacement panel of consomic Dahl SS rats.